5-151856384-C-T

Variant names:

• chr5-151856384-C-T
• rs762864856
• NM_000171.4:c.477-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000171.4(GLRA1):​c.477-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GLRA1 NM_000171.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.70
• Publications: 0 publications found

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of -34, new splice context is: acagcctccctgatgtgcAGatc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-151856384-C-T is Pathogenic according to our data. Variant chr5-151856384-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 487340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.477-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 8	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.477-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 8		NP_001139512.1
GLRA1	NM_001292000.2	c.228-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 7		NP_001278929.1
GLRA1	XM_047417105.1	c.525-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 8		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.477-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 8	1	NM_000171.4	ENSP00000274576.5
GLRA1	ENST00000455880.2	c.477-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 8	1		ENSP00000411593.2
GLRA1	ENST00000462581.6	n.*235-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 7	1		ENSP00000430595.1
GLRA1	ENST00000471351.2	n.760-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 7	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452446 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723300

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103834

Other (OTH) AF: 0.0000167 AC: 1 AN: 59950

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperekplexia 1 Pathogenic:1

-

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A homozygous 3’ splice site variation in the GLRA1 gene (chr5:151235945; C>T) that affects the invariant CT acceptor splice site of exon 5 (c.477-1G>A; ENST00000455880) was detected. This 3’ splice variation is considered pathogenic because it is not present in the 1000 Genomes database and has a minor allele frequency of less than 0.001% in the ExAC database. It is predicted to be damaging by the pathogenicity predication software such as MutationTaster and Human Splicing Finder. This region is conserved across species. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.7
GERP RS		4.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762864856; hg19: chr5-151235945;